Individuals with a high basal metabolic rate (BMR) have basal energy requirements (per kg of lean body mass) that are 10 to 20% higher than those with a low BMR. In the absence of precise regulation of food intake, these differences can have a substantial impact on body weight. The goal of the proposed research is to uncover what determines these individual differences in basal metabolic efficiency. The basic approach will be to first identify subjects with the highest and lowest ratios of BMR (assessed by indirect calorimetry) to lean body mass (assessed by total body water and potassium). These subjects then will be extensively studied to determine if they are different with respect to the following factors: thyroid hormone concentrations (free and total) and sensitivity to T3, protein turnover, Na,K ATPase activity, norepinephrine appearance rate (an index of sympathetic nervous system activity) and sensitivity to norepinephrine. Although these factors certainly contribute to some extent to basal energy requirements, there is surprisingly little information on the extent to which normal variations in these factors contribute to variability in the BMR. Total thyroid hormone levels will be measured by radioimmunoassay and the free fraction of thyroid hormones will be determined by equilibrium dialysis. Protein breakdown will be determined by measuring leucine flux, and whole body protein synthesis will be estimated from the nonoxidative disappearance of leucine. Erythrocyte 86Rb uptake and ouabain binding to muscle will be used as indices of Na,K ATPase activity. Sensitivity to T3 will be determined by measuring the increase in metabolic rate when T3 levels are elevated by exogenous hormone administration. The sensitivity to T3 with respect to protein turnover and Na,K ATPase activity will also be assessed, since these factors may mediate the hypermetabolic response to T3. Norepinephrine appearance rate will be measured by dilution of infused tracer, and sensitivity to norepinephrine will be determined by measuring the increase in metabolic rate during norepinephrine infusion. The contribution of the sympathetic nervous system to BMR also will be examined by determining how much metabolic rate declines during blockade of adrenergic receptors. These data will elucidate why individuals with similar body composition exhibit differences in basal energy expenditure, which is the largest component of total energy requirements.